NCOA4 promotes myocardial injury by upregulating ferroptosis in long-term smoking mice

Abstract

Background

Chronic smoking worsens acute myocardial infarction (AMI) severity. This study explores ferroptosis, specifically the NCOA4/FTH1 ferritinophagy pathway, in smoking-aggravated myocardial injury, seeking therapeutic targets for severe AMI in smokers.

Methods

Retrospective analysis of 525 AMI patients. Established in vivo (smoke-exposed AMI mice) and in vitro (cardiomyocytes with cigarette smoke extract + oxygen-glucose deprivation (CSE + OGD)) models. Assessed cardiac function, injury, ferroptosis markers (MDA, Fe²⁺, lipid ROS), and NCOA4/FTH1. NCOA4 was knocked down. Non-coding RNA profiling identified upstream regulators and a ceRNA network.

Results

Smoking independently predicted severe coronary lesions and post-AMI complications in patients. Chronic smoking impaired cardiac function and increased infarct size in AMI mice. CSE + OGD synergistically increased cardiomyocyte death. Ferroptosis markers and NCOA4 were elevated, while FTH1 was suppressed in smoke-exposed AMI mice and CSE + OGD cells. NCOA4 knockdown reduced cell death, ferroptosis markers, and restored FTH1. Sequencing identified 129 DE miRNAs and 317 DE lncRNAs in smoke-exposed AMI mice. qRT-PCR confirmed downregulation of miR-133a-5p, miR-186-3p, miR-21a-5p, miR-19a-3p, and upregulation of lncRNA A230028005Rik, implicating them in regulating NCOA4 via ceRNA.

Conclusion

Chronic smoking exacerbates AMI severity via NCOA4/FTH1-mediated ferroptosis. Identified ncRNAs (miR-133a-5p, miR-186-3p, miR-21a-5p, miR-19a-3p, lncRNA A230028005Rik) are promising therapeutic targets for ferroptosis-related injury in smokers.